Mechanism of RORα in promoting osteoarthritis through p53 deubiquitination-mediated chondrocyte ferroptosis

Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine

Summary Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage loss, in which iron dysregulation and ferroptosis contribute to disease progression. Here, we investigated the role of the RORα-p53 axis in regulating chondrocyte ferroptosis during OA. Transcriptomic analysis and experimental models revealed activation of ferroptosis and iron imbalance in OA cartilage, while pharmacological inhibition of ferroptosis alleviated cartilage damage. We identified p53 as a key mediator promoting ferroptotic signaling in chondrocytes and demonstrated that retinoic-acid-related orphan receptor alpha (RORα) acts upstream by stabilizing p53. Mechanistically, RORα recruits the deubiquitinase HAUSP to inhibit p53 ubiquitination, thereby enhancing ferroptotic responses. These findings define a regulatory pathway linking RORα to p53-dependent ferroptosis and cartilage degeneration and provide a potential molecular target for disease-modifying OA therapy. abs0010 Graphical abstract http://www.w3.org/1999/xlink float portrait ga1.jpg undfig1 anchor portrait graphical abs0015 Highlights • Ferroptosis is activated in OA cartilage and promotes degeneration u0010 • p53 drives chondrocyte ferroptosis and OA progression u0015 • RORα aggravates OA via p53-dependent ferroptotic signaling u0020 • RORα recruits HAUSP to stabilize p53 through deubiquitination u0025 simple ulist0010 author-highlights abs0020 Biological sciences teaser abs0025